DESCRIPTION (Verbatim from Applicant's Abstract): Increasingly, researchers understand that inflammation is critical to the development of atherosclerosis and the progression to cardiovascular (CVD) events. We hypothesize that a pathophysiologic link between systemic inflammation and CVD events is through endothelial injury and dysfunction. Endothelial dysfunction with subsequent loss of the vasodilator, anti-thrombotic, and anti-inflammatory properties of the vascular endothelium plays a dynamic role in the development of atherosclerosis and the activation of plaques culminating in CVD events. Most prior studies of inflammatory markers have been limited to small samples of highly selected patients. The relation between the markers and cardiovascular risk factors remains unclear and their relation with endothelial dysfunction and subclinical disease remains largely unexplored. Most importantly, prior studies have not demonstrated if inflammatory markers predict incident CVD in the community. Completion of such a study will require assessment of inflammatory markers in a large, well-characterized population. We propose to assess inflammatory markers in about 3,800 men and women of the Framingham Study. The markers will include inflammatory (C-reactgive protein, fibrinogen, soluble intercellular adhesion molecule-1, endothelin-1, monocyte chemotactic protein-1, tumor necrosis factor-alpha) and oxidative stress markers (8-epi-PGF 2alpha, thromboxane B2). The specific aims of this proposal are to: 1. Determine the relation between CVD risk factors and systemic markers of vascular inflammation. 2. Analyze the relations between inflammatory markers, endothelial dysfunction, and subclinical disease. 3. Relate markers of inflammation to prevalent and incident CVD events adjusting for standard risk factors. Our central hypothesis is that inflammatory markers are independent risk factors for CVD events with endothelial dysfunction operating in the causal pathway. The Framingham Study is uniquely suited for this proposal by virtue of the single site population-based design, the availability of extensive antecedent and contemporary risk factor data, and the availability of long-term, longitudinal follow-up. The proposed study provides a unique opportunity to assess the prognostic importance of inflammatory markers and is likely to yield new information that will directly improve the prevention and management of CVD.